A knock-in mouse model of gastrointestinal stromal tumor harboring Kit K641E Journal Article

Authors: Rubin, B. P.; Antonescu, C. R.; Scott-Browne, J. P.; Comstock, M. L.; Gu, Y.; Tanas, M. R.; Ware, C. B.; Woodell, J.
Article Title: A knock-in mouse model of gastrointestinal stromal tumor harboring Kit K641E
Abstract: A mouse model of gastrointestinal stromal tumor (GIST) has been developed by a knock-in gene targeting strategy, which introduced a Kit gene K641E mutation, originally identified in sporadic human GISTs and in the germ line of familial GIST syndrome patients. Homozygous and heterozygous Kit K641E mice develop gastrointestinal pathology with complete penetrance and all Kit K641E homozygotes die by age 30 weeks due to gastrointestinal obstruction by hyperplastic interstitial cells of Cajal (ICC) or GISTs. Heterozygous mice have less extensive ICC hyperplasia and smaller GISTs, suggesting a dose-response relationship between oncogenically activated Kit and ICC proliferation. Immunoprecipitation and Western blotting reveal GISTs to contain abundant phosphorylated/activated Kit. In addition to ICC hyperplasia and GISTs, homozygous Kit K641E mice exhibit loss-of-function Kit phenotypes, including white coat color, decreased numbers of dermal mast cells, and sterility, indicating that despite its oncogenic activity the mutant form cannot accomplish many activities of the wild-type gene. Kit K641E reproduces the pathology associated with the familial GIST syndrome and thus is an excellent model to study Kit pathway activation, ICC biology, GIST pathogenesis, and preclinical validations of GIST therapies and mechanisms of drug resistance. ©2005 American Association for Cancer Research.
Keywords: immunohistochemistry; signal transduction; controlled study; protein phosphorylation; gene mutation; dose response; nonhuman; cell proliferation; animal cell; mouse; phenotype; animals; mice; animal tissue; gene targeting; gastrointestinal stromal tumor; stem cell factor receptor; interstitial cell of cajal; proto oncogene; gastrointestinal stromal tumors; proto-oncogene proteins c-kit; amino acid substitution; tumor volume; embryo; animal experiment; animal model; alleles; cancer therapy; infertility; carcinogenesis; mice, transgenic; hair color; homozygosity; heterozygosity; hyperplasia; western blotting; immunoprecipitation; cell count; familial cancer; disease models, animal; glutamic acid; intestines; lysine; tumor resistance; knockout mouse; cell hyperplasia; mast cell; knock in mouse
Journal Title: Cancer Research
Volume: 65
Issue: 15
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2005-08-01
Start Page: 6631
End Page: 6639
Language: English
DOI: 10.1158/0008-5472.can-05-0891
PUBMED: 16061643
PROVIDER: scopus
Notes: --- - "Cited By (since 1996): 66" - "Export Date: 24 October 2012" - "CODEN: CNREA" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Cristina R Antonescu
    740 Antonescu